I believe this is biology's century. I've covered science and medicine for Forbes from the Human Genome Project through Vioxx to the blossoming DNA technology changing the world today.
Email me, follow me on Twitter, circle me onGoogle Plus, or subscribe to my Facebook page.

Wall Street Gets It Backward On Amgen Cholesterol Drug

Shares of Aegerion PharmaceuticalsAegerion Pharmaceuticals have risen 200% since October on hopes that the company’s drug Juxtapid, a treatment for a rare genetic disease that causes super-high cholesterol and early heart attacks, could become a big seller.

But an experimental new AmgenAmgen drug poses a threat to Juxtapid, according to data accidentally released by the European Atherosclerosis Society tonight. Thickening the plot, a Wall Street analyst and Aegerion investors have misinterpreted that data, causing Aegerion shares to rise 8.6% and Amgen shares to sink 1.5%.

Update: To be clear, Amgen’s drug looks as if it may compete with Juxtapid in about a third of the addressable patients if it gets to market. That could pose a long-term threat to Aegerion.

Amgen’s drug targets a protein called PCSK9. When this protein doesn’t work because of a rare genetic mutation, the result is dramatically lowered cholesterol and a decreased risk of heart disease. Amgen is trying to develop medicines that imitate this cholesterol-lowering effect. So is a rival partnership between Regeneron PharmaceuticalsRegeneron Pharmaceuticals and SanofiSanofi.

It wasn’t clear that Amgen’s PCSK9 drug would even work in the patients with the rare genetic disease that Juxtapid treats, called homozygous familial hypercholesterolemia or HoFH . That’s because blocking PCSK9 lowers cholesterol by blocking turning up the LDL cell receptor, which sucks cholesterol out of the blood. HoFH patients have high cholesterol because their LDL receptors don’t work. So it was unclear whether a PCSK9 drug would do anything for HoFH patients.

Earlier this evening, the EAS posted an abstract for a study testing Amgen’s PCSK9 inhibitor in eight patients with HoFH. The abstract contained data that was supposed to remain confidential until the full study is presented in Lyon, France on sometime between June 3 and June 5, and has since been taken down. Amgen spokeswoman Ashleigh Koss says that she could not comment on the data because of the EAS embargo.

Robyn Karnauskas at Deutsche Bank issued a note saying that because Amgen’s PCSK9 shot lowered LDL (low density lipoprotein) cholesterol by only 19%, compared to 50% for Juxtapid, that Amgen’s drug would not be competitive with Aegerion’s. Aegerion shares spiked following the note.

But that misreads the data. It’s true that among the eight patients tested so far, the average decrease in LDL was 19%. However, the range of data was far broader: the abstract discloses that one patient saw LDL increase 15%, while another saw it decrease 49%. Simple algebra reveals that for the other patients, the average decrease in cholesterol was about 20%. More than that, the abstract says that three patients had LDL decreases of greater than 35%. That means that patients divided into responders and non-responders, with three patients having substantial LDL decreases and five having much lower ones. Simple algebra reveals that for the other four patients, the average decrease in cholesterol was about 12%.

More than that, the abstract contains the following sentence: “Response appeared to be related to LDLr genotype and residual LDLr activity.” In other words, how well Amgen’s drug, known by the code name AMG 145, worked at decreasing LDL depended on whether the LDL receptors were working at all. That means which patients can be treated could be prospectively identified.

The Food and Drug Administration warns that Juxtapid may be toxic to the liver, and patients who take it have to be part of a program to monitor and mitigate the drug’s risks. A similar warning exists for Kynamro, a rival HoFH drug from Isis Pharmaceuticals and Sanofi. Both are very expensive . Juxtapid costs $295,000 per patient per year. Kynamro costs $176,000 per patient per year.

By contrast, Amgen’s drug, aimed at people with high cholesterol in general, is likely to cost less than $20,000 per patient per year. And it has been studied in thousands of patients without evidence of severe side effects. Beyond that, data published last year in Circulation, a medical journal, said that reducing LDL cholesterol by only 26% in HoFH patients can cut the rate of heart attacks, strokes, and other cardiovascular problems in half. Lowering LDL with drugs can also help patients avoid a procedure called apheresis in which cholesterol is filtered from their blood.

“A 20% lowering of LDL cholesterol is clinically meaningful,” says Steven Nissen, chairman of cardiology at the Cleveland Clinic. He is conducting clinical trials of AMG 145, for which he gets research support. “At the very least we can reduce the need for apheresis in these patients.”

It’s certainly true that Amgen’s drug might not be used for all HoFH patients, or that many will get both AMG 145 and Juxtapid. But to say it poses no threat goes too far. It’s more correct to take the analysis from Eun K. Yang at Jefferies, who said in a note to investors that AMG 145 is showing “potential.”

Aim: Homozygous familial hypercholesterolemia (HoFH) is a rare and serious disorder most commonly caused by substantial reduction in LDL receptor (LDLr) function. As a result, LDL-C levels are severely elevated, leading to cardiovascular disease, and often death, in childhood. Response to conventional therapies is modest, with patients receiving LDL apheresis when available. AMG 145, a monoclonal antibody to PCSK9, significantly reduces LDL-C in heterozygous FH, but the effect in HoFH is unknown. We evaluated the efficacy and safety of AMG 145 in an open-label, single arm, multicenter, dose-scheduling pilot study in patients with HoFH.Methods: Eight patients with genetically confirmed HoFH on stable drug therapy for ≥4 weeks were enrolled. AMG 145 420 mg was administered subcutaneously every 4 weeks (Q4W) for ≥12 weeks, followed by every-2-week (Q2W) dosing for an additional 12 weeks.Results: As of March 16, all 8 patients had completed 12 weeks’ treatment with AMG 145 420 mg Q4W, and 4 weeks of Q2W. LDL-C change from baseline at week 12 (Q4W) ranged from +5% to -44% (mean -16%) and at week 4 (Q2W) from +15% to -49% (mean -19%) (Table). Response appeared to be related to LDLr genotype and residual LDLr activity. Reductions were also observed in Apo B and Lp(a). AMG 145 reduced LDL-C by >35% in 3 of the 8 patients with Q2W administration. Reductions in free PCSK9 were 23% with Q4W and 90% with Q2W dosing. No serious side effects were reported. Complete data for 12 weeks of Q2W dosing will be presented at EAS.Conclusions: This pilot study, the first demonstration that PCSK9 inhibition lowers LDL-C and Lp(a) in HoFH patients, suggests that AMG 145 may provide an additional therapeutic option for patients with HoFH.

Post Your Comment

Post Your Reply

Forbes writers have the ability to call out member comments they find particularly interesting. Called-out comments are highlighted across the Forbes network. You'll be notified if your comment is called out.

Comments

I would offer that you are the one who has it backwards, are creatively misinterpreting the data, or are intentionally trying to mislead readers. Reading your article makes it appear that you want to explain away the data, to lead to a conclusion of your own making.

You claim that maybe the new AMG145 won’t be used to treat all HoFH patients, but in fact, it may not be used to treat ANY of the patients. Earlier in your own article you state

“That’s because blocking PCSK9 lowers cholesterol by blocking the LDL cell receptor, which sucks cholesterol out of the blood. HoFH patients have high cholesterol because their LDL receptors don’t work. So it was unclear whether a PCSK9 drug would do anything for HoFH patients.”

Yet at the end you assert that “Amgen’s drug might not be used for all HoFH patients” — I guess you forgot a few lines earlier you stated that it was unclear whether the drug would do anything for HoFH patients at all.

It WAS unclear before this data came out. Now we’ve seen substantial decreases in LDL in three patients. How many HoFH patients will be helped by PCSK9 drugs is an open question but it now looks like for some it will be very effective. How this will affect Aegerion years from now is an open question. But it’s wrong to say the threat is nonexistent.

I never said the threat was nonexistent. I just pointed out the inconsistency within your own article. I firmly believe that there are a host of reasons that any patient could benefit from alternative treatments (most of the reasons we don’t know and are barely beginning to understand). There could easily be a multitude of genetic specifics that could make any one medicine less effective for a single individual even though the target patient population at large responded well. There will always be a place for niche medicines. If I had to make the choice for my child though – I’d go with the more effective solution.

From what I read I find Matthew Herper’s interpretation of the data, and his suggestion, correct. A key point, it seems, is that some HoFH patients still have residual activity in their LDLr. Also, having the possibility to stratify patient populations/prospectively identify patients most likely to benefit from the treatment (based on their LDLr residual activity) would be a huge benefit. That’s if these preliminary data are confirmed, of course.

We have an interesting issue here. I believe this PCSK9 craze will end much like the CETP Inhibitor fiasco. Let’s critically evaaluate facts: 1. PCSK9 and LDLR anre intricately regulated by SREBP-2…..nature hasa reason (which is not completely understood now) why they need to be regulated so tighty 2. So far, very few people have these extremely low LDL levels due to PCSK9 mutations….why? If this was beneficial, why would it not be prevalent? Even when it is, are the mutations there to lower LDL or to deal with other external pressures, eg infectious diseases?

Look common sense and a bit of due diligence will show that even statins are pretty much useless for all-cause mortality…..why would you expect miracles from this?

I predict dire long term side effects of these PCSK9 inhibition. Let’s wait for Ph3, SHALL WE?